Project Abstract: Our lab has had a long-standing interest in understanding the molecular events underlying the activation of Rab proteins in membrane traffic, and we recently isolated Elp1p, in a genetic screen to identify physiological regulators of Rab GTPase action. Elp1p is found in a complex with five other proteins, termed the Elp complex. Our initial studies have revealed an essential cytoplasmic role for the Elp complex in the regulation of polarized exocytosis (Rahl et al. Molecular Cell 17:841-53). The work proposed here is directed at understanding the molecular mechanisms by which Elp1p and the Elongator complex regulate polarized secretion and growth. While there is a growing appreciation of the proteins involved in the biogenesis, transport and fusion of vesicles, little is understood about the factors that regulate steps of membrane traffic in response to, or coordination with, other intracellular signals. We hypothesize that Elp1p and the Elp complex act to regulate cell-surface transport and plan to address this question with a combination of several different approaches, including mutant analyses, genomic studies, biochemical and cell biological techniques and will focus on Elp1p in the model organism S. cerevisiae. Mutations in the human homolog of Elp1p, the IKAP gene, are a cause of the neurological disorder Familial Dysautonomia. The long-term goal of the research is to elucidate the mechanism of the FD disease syndrome protein encoded by IKAP.